U.S. patent application number 15/564466 was filed with the patent office on 2018-03-15 for formulation and aerosol canisters, inhalers, and the like containing the formulation.
The applicant listed for this patent is 3M INNOVATIVE PROPERTIES COMPANY. Invention is credited to YU CHEN, JAMES B. DRAKE, MEI-LING PAN, DAVID W. SCHULTZ, ENG SENG YAP, KEWU ZHU.
Application Number | 20180071231 15/564466 |
Document ID | / |
Family ID | 55755775 |
Filed Date | 2018-03-15 |
United States Patent
Application |
20180071231 |
Kind Code |
A1 |
ZHU; KEWU ; et al. |
March 15, 2018 |
FORMULATION AND AEROSOL CANISTERS, INHALERS, AND THE LIKE
CONTAINING THE FORMULATION
Abstract
Compositions containing albuterol, ipratropium, and a propellant
as well as aerosol canisters and inhalers, such as metered dose
inhalers, containing such compositions.
Inventors: |
ZHU; KEWU; (SINGAPORE,
SG) ; SCHULTZ; DAVID W.; (PINE SPRINGS, MN) ;
DRAKE; JAMES B.; (HUDSON, WI) ; CHEN; YU;
(SINGAPORE, SG) ; PAN; MEI-LING; (SINGAPORE,
SG) ; YAP; ENG SENG; (SINGAPORE, SG) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
3M INNOVATIVE PROPERTIES COMPANY |
St. Paul |
MN |
US |
|
|
Family ID: |
55755775 |
Appl. No.: |
15/564466 |
Filed: |
April 7, 2016 |
PCT Filed: |
April 7, 2016 |
PCT NO: |
PCT/US16/26313 |
371 Date: |
October 5, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62145838 |
Apr 10, 2015 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/06 20180101;
A61M 15/009 20130101; A61K 9/008 20130101; A61K 31/46 20130101;
A61K 31/137 20130101; A61M 15/0065 20130101; A61K 31/137 20130101;
A61K 2300/00 20130101; A61K 31/46 20130101; A61K 2300/00
20130101 |
International
Class: |
A61K 31/137 20060101
A61K031/137; A61K 9/00 20060101 A61K009/00; A61K 31/46 20060101
A61K031/46; A61M 15/00 20060101 A61M015/00 |
Claims
1. A composition comprising particulate albuterol or a
pharmaceutically acceptable salt or solvate thereof; particulate
ipratropium or a pharmaceutically acceptable salt or solvate
thereof at least one of 1,1,1,2,3,3,3-heptafluoropropane and
1,1,1,2-tetrafluoroethane.
2. The composition of claim 1, wherein the albuterol or a
pharmaceutically acceptable salt or solvate thereof is albuterol
sulfate.
3. The composition of claim 1 wherein the ipratropium bromide is
ipratropium bromide monohydrate.
4. The composition of claim 1 wherein the concentration of
albuterol is from 4 mg/mL to 11 mg/mL.
5. The composition of claim 1 wherein the concentration of
ipratropium is from 0.5 mg/mL to 2 mg/mL.
6. The composition of claim 1 further comprising one or more
surfactants.
7. The composition of claim 6 wherein the one or more surfactants
include at least one of oleic acid, sorbitan monooleate, sorbitan
trioleate, soya lecithin, polyethylene glycol, and
polyvinylpyrrolidone.
8. The composition of claim 6 wherein the surfactant is present
from from 0.0001 wt. % to 1 wt. %, optionally 0.001 wt. % to 0.1
wt. %, optionally 0.1 wt. %.
9. The composition of claim 1, further comprising ethanol.
10. The composition of claim 9 wherein the weight percent of
ethanol is from 0.1 wt. % to 5 wt %.
11. The composition of claim 1 wherein the albuterol concentration
is 4.19 mg/mL.
12. The composition of claim 1 wherein the concentration of
ipratropium is 0.69 mg/mL.
13. An aerosol canister comprising a composition of claim 1.
14. An inhaler comprising the aerosol canister of claim 13.
15. An inhaler of claim 14 that is a metered dose inhaler.
Description
TECHNICAL FIELD
[0001] The present disclosure relates to formulations used for, as
an example, an inhaled dosage form, as well as aerosol canisters,
inhalers, metered dose inhalers, and the like containing the
same.
BACKGROUND
[0002] Albuterol compositions, particularly for inhalers are known
in the art. Such compositions are not necessarily acceptable,
particularly when a second active agent, such as ipratropium, is
also included. In particular, prior art compositions are not always
sufficiently stable for storage.
SUMMARY
[0003] A composition can comprise particulate albuterol or a
pharmaceutically acceptable salt or solvate thereof; particulate
ipratropium or a pharmaceutically acceptable salt or solvate
thereof; and at least one of 1,1,1,2,3,3,3-heptafluoropropane (also
known as HFA-227) and 1,1,1,2-tetrafluoroethane (also known as
HFA-134a).
DETAILED DESCRIPTION
[0004] Throughout this disclosure, singular forms such as "a,"
"an," and "the" are often used for convenience; however, it should
be understood that the singular forms are meant to include the
plural unless the singular alone is explicitly specified or is
clearly indicated by the context.
[0005] Some terms used in this application have special meanings,
as defined herein. All other terms will be known to the skilled
artisan, and are to be afforded the meaning that a person of skill
in the art at the time of the invention would have given them.
[0006] Elements in this specification that are referred to as
"common," "commonly used," and the like, should be understood to be
common within the context of the compositions, articles, such as
inhalers and metered dose inhalers, and methods of this disclosure;
this terminology is not used to mean that these features are
present, much less common, in the prior art. Unless otherwise
specified, only the Background section of this Application refers
to the prior art.
[0007] The "particle size" of a single particle is the size of the
smallest hypothetical hollow sphere that could encapsulate the
particle.
[0008] The "mass median diameter" of a plurality of particles
refers to the value for a particle diameter at which 50% of the
mass of particles in the plurality of particles have a particle
size smaller than the value and 50% of the mass of particles in the
plurality of particle have a particle size greater than the
value.
[0009] The "canister size" of a plurality of particles refers to
the mass mean diameter of the plurality of particles when the
formulation is prepared.
[0010] The "ex-actuator size" of a plurality of particles refers to
the aerodynamic mass median diameter of the plurality of particles
after the plurality of particles has passed through the actuator of
an inhaler, such as a metered dose inhaler, as measured by the
procedure described in the United States Pharmacopeia
<601>.
[0011] When the concentration of albuterol is discussed in this
application, for convenience it is referred to in terms of the
concentration of the form of albuterol that is most commonly used
in this disclosure, that is, albuterol sulfate. It should therefore
be understood that if another form or salt of albuterol is used,
the concentration of that other form or salt should be calculated
on a basis relative to albuterol sulfate. A person of ordinary
skill in the relevant arts can easily perform this calculation by
comparing the molecular weight of the form or salt of albuterol
that is used to the molecular weight of albuterol sulfate.
[0012] When the concentration of ipratropium is discussed in this
application, for convenience it is referred to in terms of the
concentration of the form of ipratropium that is most commonly used
in this disclosure, ipratropium bromide monohydrate. It should
therefore be understood that if another form, hydrate, or salt of
ipratropium is used, the concentration of that other form or salt
should be calculated on a basis relative to ipratropium bromide
monohydrate. A person of ordinary skill in the relevant arts can
easily perform this calculation by comparing the molecular weight
of the form, hydrate, or salt of ipratropium that is used to the
molecular weight of ipratropium bromide monohydrate
[0013] Formulation
[0014] A pharmaceutical formulation can comprise particulate
albuterol. Albuterol is sometimes known as salbutamol. The
albuterol can be a free base, but is more typically in the form of
one or more physiologically acceptable salts or solvates. Albuterol
sulfate is most common.
[0015] The albuterol, such as albuterol sulfate, is in particulate
form. The canister size of the particles of albuterol, such as
albuterol sulfate, can be any suitable canister size. Exemplary
suitable canister sizes can be no less than 1 micrometer no less
than 1.5 micrometers, no less than 2 micrometers, no less than 2.5
micrometers, no less than 3 micrometers, no less than 3.5
micrometers, no less than 4 micrometers, or no less than 4.5
micrometers. Exemplary suitable canister sizes can also be no
greater than 5 micrometers, no greater than 4.5 micrometers, no
greater than 4.0 micrometers, no greater than 3.5 micrometers, no
greater than 3.0 micrometers, no greater than 2.5 micrometers, no
greater than 2.0 micrometers, or no greater than 1.5 micrometers. 1
micrometer to 5 micrometers is common.
[0016] The ex-actuator size of the albuterol particles, such as
albuterol sulfate particles, can be any suitable ex-actuator size.
Exemplary suitable ex-actuator sizes can be no less than 1
micrometer no less than 1.5 micrometers, no less than 2
micrometers, no less than 2.5 micrometers, no less than 3
micrometers, no less than 3.5 micrometers, no less than 4
micrometers, or no less than 4.5 micrometers. Exemplary suitable
ex-actuator sizes can also be no greater than 5 micrometers, no
greater than 4.5 micrometers, no greater than 4.0 micrometers, no
greater than 3.5 micrometers, no greater than 3.0 micrometers, no
greater than 2.5 micrometers, no greater than 2.0 micrometers, or
no greater than 1.5 micrometers. 1 micrometer to 5 micrometers is
common.
[0017] The albuterol, such as albuterol sulfate, can be present in
any suitable concentration in the formulation. When the
concentration of albuterol is expressed in terms of mg/mL, then the
concentration of albuterol can be no less than 1.5, no less than
1.6, no less than 1.7, no less than 1.8, no less than 1.9, no less
than 2.0, no less than 2.1, no less than 2.2, no less than 2.3, no
less than 2.4, no less than 2.5, no less than 2.6, no less than
2.7, no less than 2.8, no less than 2.9, no less than 3.0, no less
than 3.1, no less than 3.2, no less than 3.3, no less than 3.4, no
less than 3.5, no less than 3.6, no less than 3.7, no less than
3.8, no less than 3.9, no less than 4, no less than 4.1, no less
than 4.2, no less than 4.3, no less than 4.4, no less than 4.5, no
less than 4.6, no less than 4.8, no less than 4.9, no less than
5.0, no less than 5.1, no less than 5.1, no less than 5.2, no less
than 5.3, no less than 5.4, no less than 5.5, no less than 5.6, no
less than 5.7, no less than 5.8, no less than 5.9, no less than
6.0, no less than 6.1, no less than 6.2, no less than 6.3, no less
than 6.4, no less than 6.5, no less than 6.6, no less than 6.7, no
less than 6.8, no less than 6.9, no less than 7.0, no less than
7.1, no less than 7.2, no less than 7.3, no less than 7.4, no less
than 7.5, no less than 7.6, no less than 7.7, no less than 7.8, no
less than 7.9, no less than 8.0, no less than 8.1, no less than
8.2, no less than 8.3, no less than 8.4, no less than 8.5, no less
than 8.6, no less than 8.7, no less than 8.8, no less than 8.9, no
less than 9.0, no less than 9.1, no less than 9.2, no less than
9.3, no less than 9.4, no less than 9.5, no less than 9.6, no less
than 9.7, no less than 9.8, no less than 9.9, no less than 10.0, no
less than 10.1, no less than 10.2, no less than 10.3, no less than
10.4, no less than 10.5, no less than 10.6, no less than 10.7, no
less than 10.8, no less than 10.9, or no less than 11. Also on a
mg/mL basis, the concentration of albuterol can be no greater than
11, no greater than 10.9, no greater than 10.8, no greater than
10.7, no greater than 10.6, no greater than 10.5, no greater than
10.4, no greater than 10.3, no greater than 10.2, no greater than
10.1, no greater than 10.0, no greater than 9.9, no greater than
9.8, no greater than 9.7, no greater than 9.6, no greater than 9.5,
no greater than 9.4, no greater than 9.3, no greater than 9.2, no
greater than 9.1, no greater than 9.0, no greater than 8.9, no
greater than 8.8, no greater than 8.7, no greater than 8.6, no
greater than 8.5, no greater than 8.4, no greater than 8.3, no
greater than 8.2, no greater than 8.1, no greater than 8.0, no
greater than 7.9, no greater than 7.8, no greater than 7.7, no
greater than 7.6, no greater than 7.5, no greater than 7.4, no
greater than 7.3, no greater than 7.2, no greater than 7.1, no
greater than 7.0, no greater than 6.9, no greater than 6.8, no
greater than 6.7, no greater than 6.6, no greater than 6.5, no
greater than 6.4, no greater than 6.3, no greater than 6.2, no
greater than 6.1, no greater than 6.0, no greater than 5.9, no
greater than 5.8, no greater than 5.7, no greater than 5.6, no
greater than 5.5, no greater than 5.4, no greater than 5.3, no
greater than 5.2, no greater than 5.1, no greater than 5.0, no
greater than 4.9, no greater than 4.8, no greater than 4.7, no
greater than 4.6, no greater than 4.5, no greater than 4.4, no
greater than 4.3, no greater than 4.2, or no greater than 4.1. One
typical range is from 4 mg/mL to 11 mg/mL. Another typical range is
from 4.19 mg/mL to 10.56 mg/mL. For some applications, a
concentration of 4.13 mg/mL is employed. For other applications, a
concentration of 5.28 mg/mL is employed. For still other
applications, a concentration of 10.56 mg/mL is employed.
[0018] Ipratopium, particularly ipratropium bromide and more
particularly ipratropium bromide monohydrate can also be included.
The ipratropium, such as ipratopium bromide or ipratropium bromide
monohydrate, is also in particulate form. The canister size of the
particles of ipratropium, such as ipratopium bromide or ipratropium
bromide monohydrate, can be any suitable canister size. Exemplary
suitable canister sizes can be no less than 1 micrometer no less
than 1.5 micrometers, no less than 2 micrometers, no less than 2.5
micrometers, no less than 3 micrometers, no less than 3.5
micrometers, no less than 4 micrometers, or no less than 4.5
micrometers. Exemplary suitable canister sizes can also be no
greater than 5 micrometers, no greater than 4.5 micrometers, no
greater than 4.0 micrometers, no greater than 3.5 micrometers, no
greater than 3.0 micrometers, no greater than 2.5 micrometers, no
greater than 2.0 micrometers, or no greater than 1.5 micrometers. 1
micrometer to 5 micrometers is common.
[0019] The ex-actuator size of the ipratropium particles, such as
ipratopium bromide or ipratropium bromide monohydrate, can be any
suitable ex-actuator size. Exemplary suitable ex-actuator sizes can
be no less than 1 micrometer no less than 1.5 micrometers, no less
than 2 micrometers, no less than 2.5 micrometers, no less than 3
micrometers, no less than 3.5 micrometers, no less than 4
micrometers, or no less than 4.5 micrometers. Exemplary suitable
ex-actuator sizes can also be no greater than 5 micrometers, no
greater than 4.5 micrometers, no greater than 4.0 micrometers, no
greater than 3.5 micrometers, no greater than 3.0 micrometers, no
greater than 2.5 micrometers, no greater than 2.0 micrometers, or
no greater than 1.5 micrometers. 1 micrometer to 5 micrometers is
common.
[0020] The ipratropium can be used in any suitable concentration.
On a mg/mL basis, typical concentrations are no less than 0.3, no
less than 0.4, no less than 0.5, no less than 0.6, no less than
0.7, no less than 0.8, no less than 0.9, no less than 1.0, no less
than 1.1, no less than 1.2, no less than 1.3, no less than 1.4, no
less than 1.5, no less than 1.6, no less than 1.7, no less than
1.8, no less than 1.9, or no less than 2.0. Typical concentrations
are also no greater than 2.0, no greater than 1.9, no greater than
1.8, no greater than 1.7, no greater than 1.6, no greater than 1.5,
no greater than 1.4, no greater than 1.3, no greater than 1.2, no
greater than 1.1, no greater than 1.0, no greater than 0.9, no
greater than 0.8, no greater than 0.7, no greater than 0.6, or no
greater than 0.5. Common concentrations are from 0.5 mg/mL to 2
mg/mL, such as from 0.69 mg/mL to 1.76 mg/mL. For some
applications, a concentration of 0.69 mg/mL is used. For other
applications, a concentration of 0.88 mg/mL is used. For still
other applications, a concentration of 1.76 mg/mL is used.
[0021] A propellant can also be included in the formulation. The
propellant is typically 1,1,1,2,3,3,3,-heptafluoropropane,
1,1,1,2-tetrafluoroethane, or a combination thereof. The propellant
typically also serves to as a dispersant for the particles of
albuterol, such as albuterol sulfate, and ipratropium, such as
ipratropium bromide or ipratropium bromide monohydrate.
[0022] The particles of albuterol, such as albuterol sulfate, and
ipratropium, such as ipratropium bromide or ipratropium bromide
monohydrate, are typically not dissolved in the formulation.
Instead, the particles of albuterol, such as albuterol sulfate, and
ipratropium, such as ipratropium bromide or ipratropium bromide
monohydrate are suspended in the propellant.
[0023] In order to facilitate this suspension, additional
components can be added to the formulation. One such additional
component is ethanol. Another such additional component is a
surfactant. These additional components are not required unless
otherwise specified.
[0024] When ethanol is used, it is typically employed in relatively
low concentrations. On a weight percent basis, the amount of
ethanol used, if any, is typically no greater than 5, no greater
than 4.9, no greater than 4.8, no greater than 4.7, no greater than
4.6, no greater than 4.5, no greater than 4.4, no greater than 4.3,
no greater than 4.2, no greater than 4.1, no greater than 4.0, no
greater than 3.9, no greater than 3.8, no greater than 3.7, no
greater than 3.6, no greater than 3.5, no greater than 3.4, no
greater than 3.3, no greater than 3.2, no greater than 3.1, no
greater than 3.0, no greater than 2.9, no greater than 2.8, no
greater than 2.7, no greater than 2.6, no greater than 2.5, no
greater than 2.4, no greater than 2.3, no greater than 2.2, no
greater than 2.1, no greater than 2.0, no greater than 1.9, no
greater than 1.8, no greater than 1.7, no greater than 1.6, no
greater than 1.5, no greater than 1.4, no greater than 1.3, no
greater than 1.2, no greater than 1.1, no greater than 1.0, no
greater than 0.9, no greater than 0.8, no greater than 0.7, no
greater than 0.6, or no greater than 0.5. On a weight percent
basis, the amount of ethanol used, if any, is typically no less
than 0.5, no less than 0.6, no less than 0.7, no less than 0.8, no
less than 0.9, no less than 1.0, no less than 1.1, no less than
1.1, no less than 1.2, no less than 1.3, no less than 1.4, no less
than 1.5, no less than 1.6, no less than 1.7, no less than 1.8, no
less than 1.9, no less than 2.0, no less than 2.1, no less than
2.2, no less than 2.3, no less than 2.4, no less than 2.5, no less
than 2.6, no less than 2.7, no less than 2.8, no less than 2.9, no
less than 3.0, no less than 3.1, no less than 3.2, no less than
3.3, no less than 3 .4, no less than 3.5, no less than 3.6, no less
than 3.7, no less than 3.8, no less than 3.9, no less than 4 .0, no
less than 4.1, no less than 4.2, no less than 4.3, no less than
4.4, no less than 4.5, no less than 4.6, no less than 4.7, no less
than 4.8, no less than 4.9, or no less than 5.0. Typical ranges of
ethanol concentration, in those cases when ethanol is included, are
from 0.1 wt. % to 5 wt. %, such as from 0.5 wt. % to 4 wt. %. In
some cases, an ethanol concentration of 1 wt. % is employed.
[0025] One or more surfactant can also be used to facilitate
suspension of the particles in the formulation. However,
surfactant-free formulations can be advantageous for some purposes,
and surfactant is not required unless otherwise specified.
[0026] Any pharmaceutically acceptable surfactant can be used. Most
such surfactants are suitable for use with an inhaler. Typical
surfactants include oleic acid, sorbitan monooleate, sorbitan
trioleate, soya lecithin, polyethylene glycol,
polyvinylpyrrolidone, or combinations thereof. Oleic,
polyvinylpyrrolidone, or a combination thereof is most common. A
combination of polyvinylpyrrolidone and polyethylene glycol is also
commonly employed. When polyvinylpyrrolidone is employed, it can
have any suitable molecular weight. Examples of suitable weight
average molecular weights are from 10 to 100 kilodaltons, typically
from 10 to 50, 10 to 40, 10 to 30 or 10 to 20 kilodaltons. When
polyethylene glycol is employed, it can be any suitable grade. PEG
100 and PEG 300 are most commonly employed.
[0027] When used, the surfactant is typically present, on a weight
percent basis, in an amount no less than 0.0001, no less than 0.01,
no less than 0.02, no less than 0.03, no less than 0.04, no less
than 0.05, no less than 0.06, no less than 0.07, no less than 0.08,
no less than 0.09, no less than 0.10, no less than 0.11, no less
than 0.12, no less than 0.13, no less than 0.14, no less than 0.15,
no less than 0.16, no less than 0.17, no less than 0.18, no less
than 0.19, no less than 0.2, no less than 0.21, no less than 0.22,
no less than 0.23, no less than 0.24, no less than 0.25, no less
than 0.26, no less than 0.27, no less than 0.28, no less than 0.29,
no less than 0.3, no less than 0.4, no less than 0.5, no less than
0.6, no less than 0.7, no less than 0.8, no less than 0.9, or no
less than 1. The surfactant is also typically present, on a weight
percent basis, in an amount no greater than 1, no greater than 0.9,
no greater than 0.8, no greater than 0.7, no greater than 0.6, no
greater than 0.5, no greater than 0.4, no greater than 0.3, no
greater than 0.29, no greater than 0.28, no greater than 0.27, no
greater than 0.26, no greater than 0.25, no greater than 0.24, no
greater than 0.23, no greater than 0.22, no greater than 0.21, no
greater than 0.20, no greater than 0.19, no greater than 0.18, no
greater than 0.17, no greater than 0.16, no greater than 0.15, no
greater than 0.14, no greater than 0.13, no greater than 0.12, no
greater than 0.11, no greater than 0.10, no greater than 0.09, no
greater than 0.08, no greater than 0.07, no greater than 0.06, no
greater than 0.05, no greater than 0.04, no greater than 0.03, no
greater than 0.02, or no greater than 0.01. Concentration ranges
can be from 0.0001 wt. % to 1 wt. %, such as 0.001 wt. % to 0.1 wt.
%. Particular applications use 0.01 wt. % surfactant.
[0028] Particularly, oleic acid can be used in any of the
abovementioned concentrations. Particularly, polyvinylpyrrolidone
can be used in any of the abovementioned concentrations.
Particularly, a combination of polyethylene glycol and
polyvinylpyrrolidone can be used in any of the abovementioned
concentrations. Particularly, sorbitan trioleate can be used in any
of the abovementioned concentrations.
[0029] The formulations as described herein can be particularly
advantageous because they can stabilize the albuterol and
ipratropium contained therein. Stability of formulations of this
type can be measured by comparing the ex-actuator particle size of
albuterol, ipratropium, or both, immediately after filling the
canister to the ex-actuator particle size of the same medicament
after storage under specified conditions for a specified time.
Under this comparison, a smaller change in ex-actuator particle
size relates to a higher stability, whereas a larger change in
ex-actuator particle size relates to a lower stability.
[0030] One particular set of conditions under which stability can
be measured is storage of the pharmaceutical formulation in a
canister is a particular temperature and a particular relative
humidity, such as a temperature of 40.degree. C. and a relative
humidity of 75%. Stability can be measured after a particular
storage time. A typical storage time is 6 months. A formulation,
such as any formulation described herein, can be considered to have
good stability if there is a sufficiently small change in fine
particle mass at such particular temperatures and particular
relative humidity. Fine particle mass can be determined using a
Next Generation Impactor (NG) instrument, procedure, and
calculation, examples of which are described in detail in the
Examples section of this disclosure. A sufficiently small change in
fine particle mass can be, for example, a change that is no greater
than 15%, no greater than 14%, no greater than 13%, no greater than
12%, no greater than 11%, no greater than 10%, no greater than 9%,
no greater than 8%, no greater than 7%, no greater than 6%, no
greater than 5%, no greater than 4%, no greater than 3%, no greater
than 2%, or no greater than 1%. Typically, a change of no greater
than 5% is adequate, although greater change may be acceptable for
some applications and less change may be required for others.
[0031] Alternatively, a formulation, such as any formulation
described herein, can be considered to have good stability if there
is a sufficiently small change in ex-actuator particle size at such
particular temperatures and particular relative humidity. A
sufficiently small change in ex-actuator particle size can be, for
example, a change that is no greater than 15%, no greater than 14%,
no greater than 13%, no greater than 12%, no greater than 11%, no
greater than 10%, no greater than 9%, no greater than 8%, no
greater than 7%, no greater than 6%, no greater than 5%, no greater
than 4%, no greater than 3%, no greater than 2%, or no greater than
1%. Typically, a change of no greater than 5% is adequate, although
greater change may be acceptable for some applications and less
change may be required for others.
[0032] Any of the above-described formulations can be used with any
type of inhaler. Metered dose inhalers are most common. When the
inhaler is a metered dose inhaler, any metered dose inhaler can be
employed. Suitable metered dose inhalers are known in the art.
[0033] Typical metered dose inhalers for the pharmaceutical
formulations described herein contain an aerosol canister fitted
with a valve. The canister can have any suitable volume. The
brimful capacity canister will depend on the volume of the
formulation that is used to fill the canister. In typical
applications, the canister will have a volume from 5 mL to 500 mL,
such as, for example 10 mL to 500 mL, 25 mL to 400 mL, 5 mL to 50
mL, 8 mL to 30 mL, 10 mL to 25 mL, or 50 to 250 mL. The canister
will often have sufficient volume to contain enough medicament for
delivering an appropriate number of doses. The appropriate number
of doses is discussed herein. The valve is typically affixed, or
crimpled, onto the canister by way of a cap or ferrule. The cap or
ferrule is often made of aluminum or an aluminum alloy, which is
typically part of the valve assembly. One or more seals can be
located between the canister and the ferrule. The seals can be one
or more of O-ring seals, gasket seals, and the like. The valve is
typically a metered dose valve. Typical valve sizes range from 20
microliters to 35 microliters. Specific valve size that are
commonly employed include 25, 50, 60, and 63 microliter valve
sizes.
[0034] The container and valve typically include an actuator. Most
actuators have a patient port, which is typically a mouthpiece, for
delivering the formulation contained in the canister. The patient
port can be configured in a variety of ways depending on the
intended destination of the formulation. For example, a patient
port designed for administration to the nasal cavities will
generally have an upward slope to direct the formulation to the
nose. The actuator is most commonly made out of a plastic material.
Typical plastic materials for this purpose include at least one of
polyethylene and polypropylene. Typical MDIs have an actuator with
an orifice diameter. Any suitable orifice diameter can be used.
Typical orifice diameters are from 0.2 mm to 0.65 mm. Typical
orifice jet length is from 0.5 mm to 1 mm. Specific examples
include orifice diameters of 0.4 mm, 0.5 mm, or 0.6 mm, any of
which can have an orifice jet length of 0.8 mm.
[0035] A metered dose valve is typically present, and is often
located at least partially within the canister and at least
partially in communication with the actuator. Typical metered dose
valves include a metering chamber that is at least partially
defined by an inner valve body through which a valve stem passes.
The valve stem can be biased outwardly by a compression spring to
be in a sliding sealing engagement with an inner tank seal and
outer diaphragm seal. The valve can also include a second valve
body in the form of a body emptier. The inner valve body, which is
sometimes referred to as the primary valve body, defines, in part,
the metering chamber. The second valve body, which is sometimes
referred to as the secondary valve body, defines, in part, a
pre-metering region (sometimes called a pre-metering chamber) in
addition to serving as a bottle emptier. The outer walls of the
portion of the metered dose valve that are located within the
canister, as well as the inner walls of the canister, defined a
formulation chamber for containing the pharmaceutical
formulation.
[0036] In use, the pharmaceutical formulation passes from the
formulation chamber into the metering chamber. In moving to the
metering chamber, the formulation can pass into the above-mentioned
pre-metering chamber through an annular space between the secondary
valve body (or a flange of the secondary valve body) and the
primary valve body. Pressing the valve stem towards the interior of
the container actuates the valve, which allows the pharmaceutical
formulation to pass from the pre-metering chamber through a side
hole in the valve stem, through an outlet in the valve stem, to an
actuator nozzle, and finally through the patient port to the
patient. When the valve stem is released, the pharmaceutical
formulation enters the valve, typically to the pre-metering
chamber, through an annular space and then travels to the metering
chamber.
[0037] The pharmaceutical formulation can be placed into the
canister by any known method. The two most common methods are cold
filling and pressure filling. In a cold filling process, the
pharmaceutical formulation is chilled to an appropriate
temperature, which is typically -50.degree. C. to -60.degree. C.
for formulations that use propellant HFA 134a, HFA 227, or a
combination thereof, and added to the canister. The metered dose
valve is subsequently crimped onto the canister. When the canister
warms to ambient temperature, the vapor pressure associated with
the pharmaceutical formulation increases thereby providing an
appropriate pressure within the canister.
[0038] In a pressure filling method, the metered dose valve can be
first crimped onto the empty canister. Subsequently, the
formulation can be added through the valve into the container by
way of applied pressure. Alternatively, all of the non-volatile
components can be first added to the empty canister before crimping
the valve onto the canister. The propellant can then be added
through the valve into the canister by way of applied pressure.
[0039] Upon actuation, typical inhalers, such as metered dose
inhalers, that are filled with any one of the formulations
described herein can produce a fine particle mass of ipratropium,
particularly ipratropium bromide or ipratropium bromide monohydrate
that is from 3 mcg to 20 mcg per actuation and a fine particle mass
of albuterol, particularly albuterol sulfate, that is from 16 mcg
to 1116 mcg per actuation. In particular cases, inhalers, such as
metered dose inhalers, produce a fine particle mass of ipratropium,
particularly ipratropium bromide or ipratropium bromide monohydrate
that is from 5 mcg to 15 mcg, and a fine particle mass of
albuterol, particularly albuterol sulfate, that is from 55 mcg to
75 mcg per actuation. Fine particle mass can be calculated by the
procedure described in the Experimental section of this
disclosure.
[0040] The fine particle masses discussed above will typically
correspond to a fine particle fraction of ipratropium, particularly
ipratropium bromide or ipratropium bromide monohydrate and of
albuterol, particularly albuterol sulfate, that is from 20% to 65%,
which can be from 20% to 40% in particular cases, or from 25% to
35% in more particular cases. Fine particle fraction can be
calculated by the procedure described in the experimental section
of this disclosure.
[0041] Typical inhalers, such as metered dose inhalers, are
designed to deliver a specified number of doses of the
pharmaceutical formulation. In most cases, the specified number of
doses is from 30 to 400, such as from 120 to 250. One commonly
employed metered dose inhaler is designed to provide 120 doses;
this can be employed with any of the formulations or inhaler types
described herein. Another commonly employed metered dose inhaler is
designed to provide 240 doses; this can be employed with any of the
formulations or inhaler types described herein.
[0042] The inhaler, particularly when it is a metered dose inhaler,
can contain a dose counter for counting the number of doses.
Suitable dose counters are known in the art, and are described in,
for example, U.S. Pat. No. 8,740,014, U.S. Pat. No. 8,479,732,
US20120234317, and U.S. Pat. No. 8,814,035, all of which are
incorporated by reference for their disclosures of dose
counters.
[0043] One exemplary dose counter, which is described in detail in
U.S. Pat. No. 8,740,014 (which is hereby incorporated by reference
for its disclosure of the dose counter) has a fixed ratchet element
and a trigger element that is constructed and arranged to undergo
reciprocal movement coordinated with the reciprocal movement
between an actuation element in an inhaler and the dose counter.
The reciprocal movement typically comprises an outward stroke
(outward being with respect to the inhaler) and a return stroke.
The return stroke returns the trigger element to the position that
it was in prior to the outward stroke. A counter element is also
included in this type of dose counter. The counter element is
constructed and arranged to undergo a predetermined counting
movement each time a dose is dispensed. The counter element is
biased towards the fixed ratchet and trigger elements and is
capable of counting motion in a direction that is substantially
orthogonal to the direction of the reciprocal movement of the
trigger element.
[0044] The counter element in the above-described dose counter
comprises a first region for interacting with the trigger member.
The first region comprises at least one inclined surface that is
engaged by the trigger member during the outward stroke of the
trigger member. This engagement during the outward stroke causes
the counter element to undergo a counting motion. The counter
element also comprises a second region for interacting with the
ratchet member. The second region comprises at least one inclined
surface that is engaged by the ratchet element during the return
stroke of the trigger element causing the counter element to
undergo a further counting motion, thereby completing a counting
movement. The counter element is normally in the form of a counter
ring, and is advanced partially on the outward stroke of the
trigger element, and partially on the return stroke of the trigger
element. As the outward stroke of the trigger typically corresponds
to the depression of a valve stem that causes firing of the valve
(and, in the case of a metered dose inhaler, also meters the
contents) and the return stroke typically corresponds to the return
of the valve stem to its resting position, this dose counter allows
for precise counting of doses.
[0045] Another suitable dose counter, which is described in detail
in U.S. Pat. No. 8,479,732 (which is incorporated by reference for
its disclosure of dose counters) is specially adapted for use with
a metered dose inhaler. This dose counter includes a first count
indicator having a first indicia bearing surface. The first count
indicator is rotatable about a first axis. The dose counter also
includes a second count indicator having a second indicia bearing
surface. The second count indicator is rotatable about a second
axis. The first and second axes are disposed such that they form an
obtuse angle. The obtuse angle mentioned above can be any obtuse
angle, but is advantageously 125 to 145 degrees. The obtuse angle
permits the first and second indicia bearing surface to align at a
common viewing area to collectively present at least a portion of a
medication dosage count. One or both of the first and second
indicia bearing surfaces can be marked with digits, such that when
viewed together through the viewing area the numbers provide a dose
count. For example, one of the first and second indicia bearing
surface may have "hundreds" and "tens" place digits, and the other
with "ones" place digits, such that when read together the two
indicia bearing surfaces provide a number between 000 and 999 that
represents the dose count.
[0046] Yet another suitable dose counter is described in US
20120234317 (hereby incorporated by reference for its disclosure of
dose counters). Such a dose counter includes a counter element that
undergoes a predetermined counting motion each time a dose is
dispensed. The counting motion is typically vertical or essentially
vertical. A count indicating element is also included. The count
indicating element, which undergoes a predetermined count
indicating motion each time a dose is dispensed, includes a first
region that interacts with the counter element.
[0047] The counter element has regions for interacting with the
count indicating element. Specifically, the counter element
comprises a first region that interacts with a count indicating
element. The first region includes at least one surface that it
engaged with at least one surface of the first region of the
aforementioned count indicating element. The first region of the
counter element and the first surface of the count inducing element
are disposed such that the count indicating member completes a
count indicating motion in coordination with the counting motion of
the counter element, during and induced by the movement of the
counter element, the count inducing element undergoes a rotational
or essentially rotational movement. In practice, the first region
of the counter element or the counter indicating element can
comprise, for example, one or more channels. A first region of the
other element can comprise one or more protrusions adapted to
engage with said one or more channels.
[0048] Yet another dose counter is described in U.S. Pat. No.
8,814,035 (hereby incorporated by reference for its disclosure of
dose counters). Such a dose counter is specially adapted for use
with an inhaler with a reciprocal actuator operating along a first
axis. The dose counter includes an indicator element that is
rotatable about a second axis. The indicator element is adapted to
undergo one or more predetermined count-indicating motions when one
or more doses are dispensed. The second axis is at an obtuse angle
with respect to the first axis. The dose counter also contains a
worm rotatable about a worm axis. The worm is adapted to drive the
indicator element. It may do this, for example, by containing a
region that interacts with and enmeshes with a region of the
indicator element. The worm axis and the second axis do not
intersect and are not aligned in a perpendicular manner. The worm
axis is also, in most cases, not disposed in coaxial alignment with
the first axis. However, the first and second axes may
intersect.
[0049] At least one of the various internal components of an
inhaler, such as a metered dose inhaler, as described herein, such
as one or more of the canister, valve, gaskets, seals, O-rings, and
the like, can be coated with one or more coatings. Some of these
coatings provide a low surface energy. Such coatings are not
required because they are not necessary for the successful
operation of all inhalers.
[0050] Some coatings that can be used are described in U.S. Pat.
No. 8,414,956, U.S. Pat. No. 8,815,325 and United States Patent
Application Number US20120097159, all of which are incorporated by
reference for their disclosure of coatings for inhalers and inhaler
components.
[0051] A first acceptable coating can be provided by the following
method: [0052] a) providing one or more component of the inhaler,
such as the metered dose inhaler, [0053] b) providing a primer
composition comprising a silane having two or more reactive silane
groups separated by an organic linker group, [0054] c) providing a
coating composition comprising an at least partially fluorinated
compound, [0055] d) applying the primer composition to at least a
portion of the surface of the component, [0056] e) applying the
coating composition to the portion of the surface of the component
after application of the primer composition.
[0057] The at least partially fluorinated compound will usually
comprise one or more reactive functional groups, with the or each
one reactive functional group usually being a reactive silane
group, for example a hydrolysable silane group or a hydroxysilane
group. Such reactive silane groups allow reaction of the partially
fluorinated compound with one or more of the reactive silane groups
of the primer. Often such reaction will be a condensation
reaction.
[0058] One exemplary silane that can be used has the formula
X.sub.3-m(R.sup.1).sub.mSi--Q--Si(R.sup.2).sub.kX.sub.3-k
wherein R.sup.1 and R.sup.2 are independently selected univalent
groups, X is a hydrolysable or hydroxy group, m and k are
independently 0, 1, or 2 and Q is a divalent organic linking
group.
[0059] Useful examples of such silanes include one or a mixture of
two or more of 1,2-bis(trialkoxysilyl)ethane,
1,6-bis(trialkoxysilyl)hexane, 1,8-bis(trialkoxysilyl)octane,
1,4-bis(trialkoxysilylethyl)benzene, bis(trialkoxysilyl)itaconate,
and 4,4'-bis(trialkoxysilyl)-1,1'-diphenyl, wherein any trialkoxy
group may be independently trimethoxy or triethoxy.
[0060] The coating solvent usually comprises an alcohol or a
hydrofluoroether.
[0061] If the coating solvent is an alcohol, preferred alcohols are
C.sub.1 to C.sub.4 alcohols, in particular, an alcohol selected
from ethanol, n-propanol, or iso-propanol or a mixture of two or
more of these alcohols.
[0062] If the coating solvent is an hydrofluoroether, it is
preferred if the coating solvent comprises a C.sub.4 to C.sub.10
hydrofluoroether. Generally, the hydrofluoroether will be of
formula
C.sub.gF.sub.2g+1OC.sub.hH.sub.2h+1
wherein g is 2, 3, 4, 5, or 6 and h is 1, 2, 3 or 4. Examples of
suitable hydrofluoroethers include those selected from the group
consisting of methyl heptafluoropropylether, ethyl
heptafluoropropylether, methyl nonafluorobutylether, ethyl
nonafluorobutylether and mixtures thereof.
[0063] The polyfluoropolyether silane is typically of the
formula
R.sup.fQ.sup.1.sub.v[Q.sup.2.sub.w--[C(R.sup.4).sub.2--Si(X).sub.3-x(R.s-
up.5).sub.x].sub.y].sub.z
wherein:
[0064] R.sup.f is a polyfluoropolyether moiety; [0065] Q.sup.1 is a
trivalent linking group; [0066] each Q.sup.2 is an independently
selected organic divalent or trivalent linking group;
[0067] each R.sup.4 is independently hydrogen or a C.sub.1-4 alkyl
group;
[0068] each X is independently a hydrolysable or hydroxyl
group;
[0069] R.sup.5 is a C.sub.1-8 alkyl or phenyl group;
[0070] v and w are independently 0 or 1, x is 0 or 1 or 2; y is 1
or 2; and z is 2, 3, or 4.
[0071] The polyfluoropolyether moiety R.sup.f can comprise
perfluorinated repeating units selected from the group consisting
of --(C.sub.nF.sub.2nO)--, --(CF(Z)O)--,
--(CF(Z)C.sub.nF.sub.2nO)--, --(C.sub.nF.sub.2nCF(Z)O)--,
--(CF.sub.2CF(Z)O)--, and combinations thereof; wherein n is an
integer from 1 to 6 and Z is a perfluoroalkyl group, an
oxygen-containing perfluoroalkyl group, a perfluoroalkoxy group, or
an oxygen-substituted perfluoroalkoxy group, each of which can be
linear, branched, or cyclic, and have 1 to 5 carbon atoms and up to
4 oxygen atoms when oxygen-containing or oxygen-substituted and
wherein for repeating units including Z the number of carbon atoms
in sequence is at most 6. In particular, n can be an integer from 1
to 4, more particularly from 1 to 3. For repeating units including
Z the number of carbon atoms in sequence may be at most four, more
particularly at most 3. Usually, n is 1 or 2 and Z is an --CF.sub.3
group, more wherein z is 2, and R.sup.f is selected from the group
consisting of
--CF.sub.2O(CF.sub.2O).sub.m(C.sub.2F.sub.4O).sub.pCF.sub.2--,
--CF(CF.sub.3)O(CF(CF.sub.3)CF.sub.2O).sub.pCF(CF.sub.3)--,
--CF.sub.2O(C.sub.2F.sub.4O).sub.pCF.sub.2--,
--(CF.sub.2).sub.3O(C.sub.4F.sub.8O).sub.p(CF.sub.2).sub.3--,
--CF(CF.sub.3)--(OCF.sub.2CF(CF.sub.3)).sub.pO--C.sub.tF.sub.2t--O(CF(CF.-
sub.3)CF.sub.2O).sub.pCF(CF.sub.3)--, wherein t is 2, 3 or 4 and
wherein m is 1 to 50, and p is 3 to 40.
[0072] A cross-linking agent can be included. Typical cross-linking
agents include tetramethoxysilane; tetraethoxysilane;
tetrapropoxysilane; tetrabutoxysilane; methyl triethoxysilane;
[0073] dimethyldiethoxysilane; octadecyltriethoxysilane;
3-glycidoxy-propyltrimethoxysilane;
3-glycidoxy-propyltriethoxysilane; 3-aminopropyl-trimethoxysilane;
3-aminopropyl-triethoxysilane; bis (3-trimethoxysilylpropyl) amine;
3-aminopropyl tri(methoxyethoxyethoxy) silane; N
(2-aminoethyl)3-aminopropyltrimethoxysilane; bis
(3-trimethoxysilylpropyl) ethylenediamine;
3-mercaptopropyltrimethoxysilane; 3-mercaptopropyltriethoxysilane;
3-trimethoxysilyl-propylmethacrylate;
3-triethoxysilypropylmethacrylate; bis (trimethoxysilyl) itaconate;
allyltriethoxysilane; allyltrimethoxysilane;
3-(N-allylamino)propyltrimethoxysilane; vinyltrimethoxysilane;
vinyltriethoxysilane; and mixtures thereof.
[0074] The component to be coated can be pre-treated before
coating, typically by cleaning. Cleaning can be by way of a
solvent, typically a hydrofluoroether, e.g. HFE72DE, or an
azeotropic mixture of about 70% w/w trans-dichloroethylene; 30% w/w
of a mixture of methyl and ethyl nonafluorobutyl and
nonafluoroisobutyl ethers.
[0075] The above-described first acceptable coating is particularly
useful for coating valves components, including one or more of
valve stems, bottle emptiers, springs, and tanks, as well as
canisters, such as metered dose inhalers, as described herein. This
coating system can be used with any type of inhaler and any
formulation described herein.
[0076] A second type of coating that can be used comprises a
polyphenylsulphone. The polyphenylsulphone typically has the
following chemical structure
##STR00001##
[0077] In this structure, n is the number of repeat units, which is
typically sufficient to provide a weight average molecular weight
from 10,000 to 80,000 daltons, for example, from 10,000 to 30,000
daltons.
[0078] Other polymers, such as polyethersulphones, fluoropolymers
such as PTFE, FEP, or PFA, can also be included. However, such
other polymers are optional, and it is often advantageous to
exclude them.
[0079] Polyphenylsulphones can be difficult to apply by a solvent
casting process. Thus, a special solvent system that is viable for
use in a manufacturing setting can be employed for coating the
polyphenylsulphones. On such solvent system employs a (1) first
solvent that has a Hildebrand Solubility Parameter of at least 20.5
MPa.sup.0.5 and at most 25 MPa.sup.0.5, such as from 21 MPa.sup.0.5
to 23.5 MPa.sup.0.5; and (2) at least 20% by volume, often greater
than 70% or greater than 80% by volume, of at least one 5-membered
aliphatic, cyclic, or heterocyclic ketone based on the total volume
of the solvent system. Optionally, a third component, namely a
linear aliphatic ketone, can be included in amounts less than 5% by
volume of the total volume of the solvent system.
[0080] Any first solvent that has a Hildebrand Solubility Parameter
of at least 20.5 MPa.sup.0.5 and at most 25 MPa.sup.0.5 can be
used, so long as the other components of the solvent system are as
stated above. Some such first solvents are also -membered
aliphatic, cyclic, or heterocyclic ketones, in which case the first
solvent and the -membered aliphatic, cyclic, or heterocyclic ketone
can be the same material. Other such solvents include
acetonitrile.
[0081] The 5-membered aliphatic, cyclic, or heterocyclic ketone is
typically a gamma lactone, such as gamma-butyrolactone, or a gamma
lactam, such as a pyrolidone like 2-pyrrolidone, or an alkyl
substituted 2-pyrrolidone like N-alkyl-2-pyrrolidones such as
N-methyl-2-pyrrolidine (sometimes known by the acronym NMP). Other
examples of 5-membered aliphatic, cyclic, or heterocyclic ketone
that can be used include 2-methyl cyclopentanone, 2-ethyl
cyclopentanone, and 2-[1-(5-methyl-2-furyl)butyl]cyclopentanone.
Cyclopentanone is the most commonly used material.
[0082] The optional linear aliphatic ketone can be any linear
aliphatic ketone, and is typically acetone, although methyl ethyl
ketone is also frequently employed.
[0083] The above-described second acceptable coating can be used on
any type of inhaler, but is particularly useful for components of
metered dose inhalers.
[0084] A third acceptable coating can be used to lower the surface
energy of any component of an inhaler, such as a metered dose
inhaler, but is particularly useful for valve stems, particularly
those made of acetal polymer, as well as for stainless steel or
aluminum components, particularly those used in canisters.
[0085] Such a coating can be formed on a component of an inhaler by
the following process: [0086] a) forming a non-metal coating on at
least a portion of a surface of the medicinal inhalation device or
a component of a medicinal inhalation device, respectively, said
coating having at least one functional group; [0087] b) applying to
at least a portion of a surface of the non-metal coating a
composition comprising an at least partially fluorinated compound
comprising at least one functional group; and [0088] c) allowing at
least one functional group of the at least partially fluorinated
compound to react with at least one functional group of the
non-metal coating to form a covalent bond.
[0089] The at least one functional group of the non-metal coating
is typically a hydroxyl group or silanol group. In most cases, the
non-metal coating has a plurality of functional groups,
particularly silanol groups, and can be formed, for example by
plasma coating an organosilicone with silanol groups on the inhaler
or one or more inhaler components. Typical organosilicon compounds
include trimethylsilane, triethylsilane, trimethoxysilane,
triethoxysilane, tetramethylsilane, tetraethylsilane,
tetramethoxysilane, tetraethoxysilane, hexamethylcyclotrisiloxane,
tetramethylcyclotetrasiloxane, tetraethylcyclotetrasiloxane,
octamethylcyclotetrasiloxane, hexamethyldisiloxane,
bistrimethylsilylmethane, and mixtures thereof. Most commonly, one
or more of trimethylsilane, triethylsilane, tetramethylsilane,
tetraethylsilane, bistrimethylsilylmethane are employed, with
tetramethylsilane being most common. In addition to the
organosilicon, the plasma can contain one or more of oxygen, a
silicon hydride, particularly silicon tetrahydride, disilane, or a
mixture thereof, or both. After deposition, the non-metal coating
can be a diamond like glass or carbon like glass containing, on a
hydrogen free basis, at 20 atomic percent or more of carbon and 30
atomic percent of more of silicon and oxygen combined.
[0090] The non-metal coating is often exposed to an oxygen plasma
or corona treatment before applying the partially fluorinated
compound. Most typically, an oxygen plasma treatment under ion
bombardment conditions is employed.
[0091] The at least partially fluorinated compound often contains
one or more hydrolysable groups, such as oxyalkly silanes,
typically ethyoxy or methoxy silanes. A polyfluoropolyether
segment, which in particular cases is a perfluorinated
polyfluoroether, is typically used. Poly(perfluoroethylene) glycol
is most common. Thus, the at least partially fluorinated compound
can include a polyfluropolyether linked to one or more functional
silanes by way of, for example, a carbon-silicon, nitrogen-silicon,
or sulfer-silicon.
[0092] Examples of at least partially fluorinated compounds that
can be used include those having the following formula:
R.sub.f[Q--[C(R).sub.2--Si(Y).sub.3-x(R.sup.1a).sub.x].sub.y].sub.z
[0093] wherein: [0094] R.sub.f is a monovalent or multivalent
polyfluoropolyether segment; [0095] Q is an organic divalent or
trivalent linking group; [0096] each R is independently hydrogen or
a C.sub.1-4 alkyl group; [0097] each Y is independently a
hydrolysable group; [0098] R.sup.1a is a C.sub.1-8 alkyl or phenyl
group; [0099] x is 0 or 1 or 2; [0100] y is 1 or 2; and [0101] z is
1, 2, 3, or 4.
[0102] Typically, R.sub.f, comprises perfluorinated repeating units
selected from the group consisting of --(C.sub.nF.sub.2nO)--,
--(CF(Z)O)--, --(CF(Z)C.sub.nF.sub.2nO)--,
--(C.sub.nF.sub.2nCF(Z)O)--, --(CF.sub.2CF(Z)O)--, and combinations
thereof; wherein n is an integer from 1 to 6 and Z is a
perfluoroalkyl group, an oxygen-containing perfluoroalkyl group, a
perfluoroalkoxy group, or an oxygen-substituted perfluoroalkoxy
group, each of which can be linear, branched, or cyclic, and have 1
to 5 carbon atoms and up to 4 oxygen atoms when oxygen-containing
or oxygen-substituted and wherein for repeating units including Z
the number of carbon atoms in sequence is at most 6. Particular
examples of this compound are those where z is 1, R.sub.f is
selected from the group consisting of
C.sub.3F.sub.7O(CF(CF.sub.3)CF.sub.2O).sub.pCF(CF.sub.3)--,
CF.sub.3O(C.sub.2F.sub.4O).sub.pCF.sub.2--,
--C.sub.3F.sub.7O(CF(CF.sub.3)CF.sub.2O).sub.pCF.sub.2CF.sub.2--,
C.sub.3F.sub.7O(CF.sub.2CF.sub.2CF.sub.2O).sub.pCF.sub.2CF.sub.2--,
C.sub.3F.sub.7O(CF.sub.2CF.sub.2CF.sub.2O).sub.pCF(CF.sub.3)-- and
CF.sub.3O(CF.sub.2CF(CF.sub.3)O).sub.p(CF.sub.2O)X--, wherein X is
CF.sub.2--, C.sub.2F.sub.4--,
[0103] C.sub.3F.sub.6--, C.sub.4F.sub.8-- and wherein the average
value of p is 3 to 50. Other particular examples include those
wherein z is 2, R.sub.f is selected from the group consisting of
--CF.sub.2O(CF.sub.2O).sub.m(C.sub.2F.sub.4O).sub.pCF.sub.2--,
--CF(CF.sub.3)O(CF(CF.sub.3)CF.sub.2O).sub.pCF(CF.sub.3)--,
--CF.sub.2O(C.sub.2F.sub.4O).sub.pCF.sub.2--,
--(CF.sub.2).sub.3O(C.sub.4F.sub.8O).sub.p(CF.sub.2).sub.3--,
--CF(CF.sub.3)--(OCF.sub.2CF(CF.sub.3)).sub.pO--C.sub.5F.sub.2t--O(CF(CF.-
sub.3)CF.sub.2O).sub.pCF(CF.sub.3)--, wherein t is 2, 3 or 4 and
wherein m is 1 to 50, and p is 3 to 40. Most commonly R.sub.f is
one of
--CF.sub.2O(CF.sub.2O).sub.m(C.sub.2F.sub.4O).sub.pCF.sub.2--,
--CF.sub.2O(C.sub.2F.sub.4O).sub.pCF.sub.2--, and
--CF(CF.sub.3)--(OCF.sub.2CF(CF.sub.3)).sub.pO--(C.sub.tF.sub.2t)--O(CF(C-
F.sub.3)CF.sub.2O).sub.pCF(CF.sub.3)--, t is 2, 3, or 4, and the
average value of m+p or p+p or p is from about 4 to about 24. Q is
commonly selected from the group consisting of
--C(O)N(R)--(CH.sub.2).sub.k--,
--S(O).sub.2N(R)--(CH.sub.2).sub.k--, --(CH.sub.2).sub.k--,
--CH.sub.2O--(CH.sub.2).sub.k--, --C(O)S--(CH.sub.2).sub.k--,
--CH.sub.2OC(O)N(R)--(CH.sub.2).sub.k--, and
##STR00002##
when R is hydrogen or C.sub.1-4 alkyl, and k is 2 to about 25. In
other common cases, Q is selected from the group consisting of
--C(O)N(R)(CH.sub.2).sub.2--, --OC(O)N(R)(CH.sub.2).sub.2--,
--CH.sub.2O(CH.sub.2).sub.2--, or
--CH.sub.2--OC(O)N(R)--(CH.sub.2).sub.2--, R is hydrogen or
C.sub.1-4 alkyl, and y is 1.
[0104] Upon applying appropriate at least partially fluorinated
compounds to the non-metallic coating, at least one covalent bond
can form between the two, thereby completing the coating.
[0105] Yet another suitable coating is fluorinated ethylene
propylene copolymer, sometimes known as FEP. FEP coatings are
particularly useful for coating one or more internal surfaces of a
canister, and can be used in association with
LIST OF EXEMPLARY EMBODIMENTS
[0106] The following embodiments are meant to be illustrative, and
are not intended to be limiting unless otherwise specified. [0107]
1. A composition comprising [0108] particulate albuterol or a
pharmaceutically acceptable salt or solvate thereof; [0109]
particulate ipratropium or a pharmaceutically acceptable salt or
solvate thereof at least one of 1,1,1,2,3,3,3-heptafluoropropane
and 1,1,1,2-tetrafluoroethane. [0110] 2. The composition of
embodiment 1, consisting essentially of [0111] particulate
albuterol or a pharmaceutically acceptable salt or solvate thereof;
[0112] ipratropium b or a pharmaceutically acceptable salt or
solvate thereof at least one of 1,1,1,2,3,3,3-heptafluoropropane
and 1,1,1,2-tetrafluoroethane. [0113] 3. The composition of any
preceding embodiment, wherein the albuterol or a pharmaceutically
acceptable salt or solvate thereof is albuterol sulfate. [0114] 4.
The composition of any preceding embodiment, wherein the
ipratropium or a pharmaceutically acceptable salt or solvate
thereof is ipratropium bromide. [0115] 5. The composition of
embodiment 4 wherein the ipratropium bromide is ipratropium bromide
monohydrate. [0116] 6. The composition of any preceding embodiment,
wherein the canister particle size of the albuterol is no less than
1 micrometer no less than 1.5 micrometers, no less than 2
micrometers, no less than 2.5 micrometers, no less than 3
micrometers, no less than 3.5 micrometers, no less than 4
micrometers, or no less than 4.5 micrometers. [0117] 7. The
composition of any preceding embodiment, wherein the canister
particle size of the albuterol is no greater than 5 micrometers, no
greater than 4.5 micrometers, no greater than 4.0 micrometers, no
greater than 3.5 micrometers, no greater than 3.0 micrometers, no
greater than 2.5 micrometers, no greater than 2.0 micrometers, or
no greater than 1.5 micrometers. [0118] 8. The composition of any
preceding embodiment, wherein the canister size of the ipratropium
is no less than 1 micrometer no less than 1.5 micrometers, no less
than 2 micrometers, no less than 2.5 micrometers, no less than 3
micrometers, no less than 3.5 micrometers, no less than 4
micrometers, or no less than 4.5 micrometers. [0119] 9. The
composition of any preceding embodiment, wherein the canister size
of the ipratropium is no greater than 5 micrometers, no greater
than 4.5 micrometers, no greater than 4.0 micrometers, no greater
than 3.5 micrometers, no greater than 3.0 micrometers, no greater
than 2.5 micrometers, no greater than 2.0 micrometers, or no
greater than 1.5 micrometers. [0120] 10. The composition of any
preceding embodiment, wherein the concentration of albuterol, on a
mg/mL basis, is no less than 4, no less than 4.1, no less than 4.2,
no less than 4.3, no less than 4.4, no less than 4.5, no less than
4.6, no less than 4.8, no less than 4.9, no less than 5.0, no less
than 5.1, no less than 5.1, no less than 5.2, no less than 5.3, no
less than 5.4, no less than 5.5, no less than 5.6, no less than
5.7, no less than 5.8, no less than 5.9, no less than 6.0, no less
than 6.1, no less than 6.2, no less than 6.3, no less than 6.4, no
less than 6.5, no less than 6.6, no less than 6.7, no less than
6.8, no less than 6.9, no less than 7.0, no less than 7.1, no less
than 7.2, no less than 7.3, no less than 7.4, no less than 7.5, no
less than 7.6, no less than 7.7, no less than 7.8, no less than
7.9, no less than 8.0, no less than 8.1, no less than 8.2, no less
than 8.3, no less than 8.4, no less than 8.5, no less than 8.6, no
less than 8.7, no less than 8.8, no less than 8.9, no less than
9.0, no less than 9.1, no less than 9.2, no less than 9.3, no less
than 9.4, no less than 9.5, no less than 9.6, no less than 9.7, no
less than 9.8, no less than 9.9, no less than 10.0, no less than
10.1, no less than 10.2, no less than 10.3, no less than 10.4, no
less than 10.5, no less than 10.6, no less than 10.7, no less than
10.8, no less than 10.9, or no less than 11. [0121] 11. The
composition of any preceding embodiment, wherein the concentration
of albuterol, on a mg/mL basis, is no greater than 11, no greater
than 10.9, no greater than 10.8, no greater than 10.7, no greater
than 10.6, no greater than 10.5, no greater than 10.4, no greater
than 10.3, no greater than 10.2, no greater than 10.1, no greater
than 10.0, no greater than 9.9, no greater than 9.8, no greater
than 9.7, no greater than 9.6, no greater than 9.5, no greater than
9.4, no greater than 9.3, no greater than 9.2, no greater than 9.1,
no greater than 9.0, no greater than 8.9, no greater than 8.8, no
greater than 8.7, no greater than 8.6, no greater than 8.5, no
greater than 8.4, no greater than 8.3, no greater than 8.2, no
greater than 8.1, no greater than 8.0, no greater than 7.9, no
greater than 7.8, no greater than 7.7, no greater than 7.6, no
greater than 7.5, no greater than 7.4, no greater than 7.3, no
greater than 7.2, no greater than 7.1, no greater than 7.0, no
greater than 6.9, no greater than 6.8, no greater than 6.7, no
greater than 6.6, no greater than 6.5, no greater than 6.4, no
greater than 6.3 , no greater than 6.2, no greater than 6.1, no
greater than 6.0, no greater than 5.9, no greater than 5.8, no
greater than 5.7, no greater than 5.6, no greater than 5.5, no
greater than 5.4, no greater than 5.3, no greater than 5.2, no
greater than 5.1, no greater than 5.0, no greater than 4.9, no
greater than 4.8, no greater than 4.7, no greater than 4.6, no
greater than 4.5, no greater than 4.4, no greater than 4.3, no
greater than 4.2, or no greater than 4.1. [0122] 13. The
composition of any preceding embodiment, wherein the concentration
of albuterol is from 4 mg/mL to 11 mg/mL. [0123] 14. The
composition of any preceding embodiment, wherein the concentration
of albuterol is from 4.19 mg/mL to 10.56 mg/mL. [0124] 15. The
composition of any preceding embodiment, wherein the concentration
of ipratropium is, on a mg/mL basis, no less than 0.5, no less than
0.6, no less than 0.7, no less than 0.8, no less than 0.9, no less
than 1.0, no less than 1.1, no less than 1.2, no less than 1.3, no
less than 1.4, no less than 1.5, no less than 1.6, no less than
1.7, no less than 1.8, no less than 1.9, or no less than 2.0.
[0125] 16. The composition of any preceding embodiment, wherein the
concentration of ipratropium is, on a mg/mL basis, no greater than
2.0, no greater than 1.9, no greater than 1.8, no greater than 1.7,
no greater than 1.6, no greater than 1.5, no greater than 1.4, no
greater than 1.3, no greater than 1.2, no greater than 1.1, no
greater than 1.0, no greater than 0.9, no greater than 0.8, no
greater than 0.7, no greater than 0.6, or no greater than 0.5.
[0126] 17. The composition of any preceding embodiment wherein the
concentration of ipratropium is from 0.5 mg/mL to 2 mg/mL. [0127]
18. The composition of any preceding embodiment wherein the
concentration of ipratropium is as from 0.69 mg/mL to 1.76 mg/mL.
[0128] 19. The composition of any preceding embodiment further
comprising one or more surfactants. [0129] 20. The composition of
any preceding embodiment wherein the one or more surfactants
include at least one of oleic acid, sorbitan monooleate, sorbitan
trioleate, soya lecithin, polyethylene glycol, and
polyvinylpyrrolidone. [0130] 21. The composition of embodiment 20,
wherein the one or more surfactants include at least one of oleic
acid and polyvinylpyrrolidone. [0131] 22. The composition of
embodiment 21, wherein polyvinylpyrrolidone has a weight average
molecular weight from 10 to 100 kilodaltons, optionally from 10 to
50, optionally from 10 to 40 kilodaltons, optionally from 10 to 30
kilodaltons, or optionally 10 to 20 kilodaltons. [0132] 23. The
composition of any of embodiments 20-22 wherein the surfactant is
present, on a weight percent basis, in an amount no less than
0.0001, no less than 0.01, no less than 0.02, no less than 0.03, no
less than 0.04, no less than 0.05, no less than 0.06, no less than
0.07, no less than 0.08, no less than 0.09, no less than 0.10, no
less than 0.11, no less than 0.12, no less than 0.13, no less than
0.14, no less than 0.15, no less than 0.16, no less than 0.17, no
less than 0.18, no less than 0.19, no less than 0.2, no less than
0.21, no less than 0.22, no less than 0.23, no less than 0.24, no
less than 0.25, no less than 0.26, no less than 0.27, no less than
0.28, no less than 0.29, no less than 0.3, no less than 0.4, no
less than 0.5, no less than 0.6, no less than 0.7, no less than
0.8, no less than 0.9, or no less than 1. [0133] 24. The
composition of any of embodiments 20-23 wherein the surfactant is
present, on a weight percent basis, in an amount no greater than 1,
no greater than 0.9, no greater than 0.8, no greater than 0.7, no
greater than 0.6, no greater than 0.5, no greater than 0.4, no
greater than 0.3, no greater than 0.29, no greater than 0.28, no
greater than 0.27, no greater than 0.26, no greater than 0.25, no
greater than 0.24, no greater than 0.23, no greater than 0.22, no
greater than 0.21, no greater than 0.20, no greater than 0.19, no
greater than 0.18, no greater than 0.17, no greater than 0.16, no
greater than 0.15, no greater than 0.14, no greater than 0.13, no
greater than 0.12, no greater than 0.11, no greater than 0.10, no
greater than 0.09, no greater than 0.08, no greater than 0.07, no
greater than 0.06, no greater than 0.05, no greater than 0.04, no
greater than 0.03, no greater than 0.02, or no greater than 0.01.
[0134] 24. The composition of any of embodiments 1-23, wherein the
surfactant is present from from 0.0001 wt. % to 1 wt. %, optionally
0.001 wt. % to 0.1 wt. %, optionally 0.1 wt. %. [0135] 25. The
composition of any of the preceding embodiments, further comprising
ethanol. [0136] 26. The composition of embodiment 25 wherein the
weight percent of ethanol is no greater than 5, no greater than
4.9, no greater than 4.8, no greater than 4.7, no greater than 4.6,
no greater than 4.5, no greater than 4.4, no greater than 4.3, no
greater than 4.2, no greater than 4.1, no greater than 4.0, no
greater than 3.9, no greater than 3.8, no greater than 3.7, no
greater than 3.6, no greater than 3.5, no greater than 3.4, no
greater than 3.3, no greater than 3.2, no greater than 3.1, no
greater than 3.0, no greater than 2.9, no greater than 2.8, no
greater than 2.7, no greater than 2 6, no greater than 2.5, no
greater than 2.4, no greater than 2.3, no greater than 2.2, no
greater than 2.1, no greater than 2.0, no greater than 1.9, no
greater than 1.8, no greater than 1.7, no greater than 1.6, no
greater than 1.5, no greater than 1.4, no greater than 1.3, no
greater than 1.2, no greater than 1.1, no greater than 1.0, no
greater than 0.9, no greater than 0.8, no greater than 0.7, no
greater than 0.6, or no greater than 0.5. [0137] 27. The
composition of any of embodiments 25-26, wherein the weight percent
of ethanol is no less than 0.5, no less than 0.6, no less than 0.7,
no less than 0.8, no less than 0.9, no less than 1.0, no less than
1.1, no less than 1.2, no less than 1.3, no less than 1.4, no less
than 1.5, no less than 1.6, no less than 1.7, no less than 1.8, no
less than 1.9, no less than 2.0, no less than 2.1, no less than
2.2, no less than 2.3, no less than 2.4, no less than 2.5, no less
than 2.6, no less than 2.7, no less than 2.8, no less than 2.9, no
less than 3.0, no less than 3.1, no less than 3.2, no less than
3.3, no less than 3 .4, no less than 3.5, no less than 3.6, no less
than 3.7, no less than 3.8, no less than 3.9, no less than 4 .0, no
less than 4.1, no less than 4.2, no less than 4.3, no less than
4.4, no less than 4.5, no less than 4.6, no less than 4.7, no less
than 4.8, no less than 4.9, or no less than 5.0. [0138] 28. The
composition of any of embodiments 25-27 wherein the weight percent
of ethanol is from 0.1 wt. % to 5 wt. %, optionally from 0.5 wt. %
to 4 wt. %. [0139] 29. The composition of embodiment 28, wherein
the weight percent of ethanol is 1 wt. % is employed. [0140] 30.
The composition of any preceding embodiment wherein the albuterol
concentration is 4.19 mg/mL. [0141] 31. The composition of any of
embodiments 1-29 wherein the albuterol concentration is 5.28 mg/mL.
[0142] 32. The composition of any of embodiments 1-29 wherein the
albuterol concentration is 10.56 mg/mL. [0143] 33. The composition
of any of embodiments 30-32 wherein the albuterol is albuterol
sulfate. [0144] 34. The composition of any preceding embodiment
wherein the concentration of ipratropium is 0.69 mg/mL. [0145] 35.
The composition of any of embodiments 1-33 wherein the
concentration of ipratropium is 0.88 mg/mL. [0146] 36. The
composition of any of embodiments 1-33 wherein the concentration of
ipratropium is 1.76 mg/mL. [0147] 37. The composition of any of
embodiments 34-36 wherein the ipratropium is ipratropium bromide.
[0148] 38. The composition of embodiment 37 wherein the ipratropium
bromide is ipratropium bromide monohydrate. [0149] 39. The
composition of any preceding embodiment wherein the composition is
stable after six months of storage inside an aerosol canister at a
temperature of 40.degree. C. and a relative humidity of 75%. [0150]
40. The composition of any preceding embodiment, wherein either
[0151] a) the change in fine particle size after storage for six
months in an aerosol canister fitted with an actuator is no greater
than 15%, no greater than 14%, no greater than 13%, no greater than
12%, no greater than 11%, no greater than 10%, no greater than 9%,
no greater than 8%, no greater than 7%, no greater than 6%, no
greater than 5%, no greater than 4%, no greater than 3%, no greater
than 2%, or no greater than 1%; or [0152] b) the change in fine
particle mass after storage for six months in an aerosol canister
fitted with an actuator is no greater than 15%, no greater than
14%, no greater than 13%, no greater than 12%, no greater than 11%,
no greater than 10%, no greater than 9%, no greater than 8%, no
greater than 7%, no greater than 6%, no greater than 5%, no greater
than 4%, no greater than 3%, no greater than 2%, or no greater than
1%; or [0153] c) both a) and b). [0154] 41. The composition of
embodiment 40 wherein the change in fine particle size is no
greater than 5%, or wherein the change in fine particle mass is no
greater than 5%, or wherein the change in fine particle size and
fine particle mass are both no greater than 5%. [0155] 42. An
aerosol canister containing a formulation of any preceding
embodiment. [0156] 43. The aerosol canister of embodiment 42
comprising at least one surface having a primer composition
comprising a silane having two or more reactive silane groups
separated by an organic linker group disposed thereon, wherein the
primer composition has a coating composition comprising an at least
partially fluorinated compound disposed thereon. [0157] 44. The
aerosol canister of embodiment 43, wherein the at least partially
fluorinated compound is an at least partially fluorinated
polyethersilane.
[0158] 45. An aerosol canister of embodiment 42 comprising at least
one surface having a coating comprising polyphenylsulphone. [0159]
46. An aerosol canister of embodiment 42 comprising at least one
surface having a coating comprising a diamond like glass or carbon
like glass. [0160] 47. An inhaler comprising the formulation of any
of embodiments 1-39 or the aerosol canister of embodiment 40.
[0161] 48. The inhaler of embodiment 47 that is a metered dose
inhaler. [0162] 49. The inhaler of any of embodiments 47-48
comprising a valve stem. [0163] 50. The inhaler of any of
embodiments 47-49 comprising a dose counter.
EXAMPLES
[0164] HFA-134a (1,1,1,2-tetrafluoroethane) and HFA-227
(1,1,1,2,3,3,3-heptafluoropropane) were obtained from the DuPont
Corporation (Wilmington, Del.) or the Solvay Corporation (Brussels,
Belgium). Ipratropium bromide monohydrate was obtained from Vamsi
Labs Ltd. (Solapur, India) or Sifavitor-Infa Group (Milan, Italy).
Albuterol sulphate was obtained Vamsi Labs Ltd. (Solapur, India) or
Teva Pharmaceutical Products Ltd. (North Wales, Pa.). Ethanol was
obtained from Hayman Specialty Products (Witham, England),
Sigma-Aldrich Corporation (St. Louis, Mo.), or Pharmco-AAPER
(Brookfield, Conn.). Span-85 (sorbitan trioleate) and PVP-10
(polyvinylpyrrolidone of average molecular weight 10,000) were
obtained from Sigma-Aldrich Corporation (St. Louis, Mo.). Oleic
acid was obtained from Merck-Millipore (Darmstadt, Germany).
Example 1
[0165] Metered dose inhalers (MDIs) were prepared using 15 mL deep
drawn aluminum canisters (3M Corporation, Clitheroe, UK), 50
microliter SPRAYMISER type valves fitted with EPDM
(ethylene-propylene diene terpolymer elastomer) diaphragm seals (3M
Corporation), and 0.6 mm orifice diameter actuators (part No.
HP-22817-1MA, RPC-Formatec GmbH, Mellrichstadt, Germany). Albuterol
sulfate and ipratropium bromide monohydrate were each micronized to
provide a mass median diameter (MMD) range of about 1-5 microns.
The canisters were cold filled with the suspension formulation of
Table 1. The bulk formulation for cold filling individual canisters
was prepared by combining albuterol sulfate and ipratropium bromide
monohydrate with a portion of the HFA-227 propellant (about half of
the total propellant) in a vessel chilled to less than -50.degree.
C. The suspension was high shear mixed for 5-10 minutes using a
Silverson mixer (Silverson, East Longmeadow, Mass.). The remaining
propellant was then added to the chilled vessel and high shear
mixing was continued for an additional 10 minutes.
Example 2
[0166] Metered dose inhalers were prepared according to the
description of Example 1 with the exception that the internal
surface of each canister was coated with FEP (fluorinated ethylene
propylene copolymer).
TABLE-US-00001 TABLE 1 Suspension Formulation of Examples 1 and 2
Formulation Ingredient Amount (in Percent by Weight) Albuterol
sulfate 0.335 Ipratropium Bromide Monohydrate 0.060 HFA-227
99.605
Next Generation Impactor (NGI) Studies
[0167] The aerodynamic particle size distribution emitted from each
MDI was evaluated using a Next Generation Impactor Instrument (MSP
Corporation, Shoreview, Minn.). For each test, an MDI was attached
to the throat component (USP Inlet) of the NGI instrument and
actuated 10 times into the instrument. Immediately prior to
attachment, the MDI was primed by actuating 3 times. The flow rate
through the instrument during testing was regulated at 30 L/minute.
The test sample (albuterol sulfate and ipratropium bromide)
deposited on the valve stem, actuator, throat assembly (USP inlet),
individual collection cups 1-7, micro-orifice collector (MOC), and
final filter component was collected by rinsing each individual
component with a known volume of collection solvent (30/70 (v/v)
acidified water (pH 2.6, H.sub.3PO.sub.4)/acetonitrile). The
recovered samples were then analyzed for sample content using an
HPLC assay with a reference standard curve. An Agilent 1200 HPLC
instrument with a UV detector (220 nm) and a Zorbax SB-C18, micron,
4.6-150 mm column (40.degree. C. column temp) was used (Agilent
Technologies, Santa Clara, Calif.). A 2-component gradient mobile
phase was used with 0.2% aqueous HClO.sub.4 as the first component
and acetonitrile as the second component (gradient 5% acetonitrile
to 90% acetonitrile). The injection volume was 20 microliters and
the flow rate was 1 mL/min. The MDIs were stored in an inverted
orientation (i.e. valve positioned down) in a 4.degree.
C./40.degree. C. cycling chamber (cycling rate 6 hours) for a
period of either 5, 6 or 9 weeks. MDIs were tested on the day
prepared (Day 0) and after either 5, 6 or 9 weeks of storage. In
Table 2, the total Ex-valve content, fine particle mass (FPM), and
fine particle fraction (FPF) data for albuterol sulfate is
presented. In Table 3, the corresponding data for ipratropium
bromide is presented. At each time point three individual MDIs were
tested and the result is presented as the mean value with standard
deviation [SD]. Total Ex-valve content was determined as the sum of
the sample content from all of the twelve analyzed components
(valve stem through filter) (reported as micrograms/actuation). FPM
(Fine Particle Mass) was determined as the sum of the sample
content determined for Cups 3-7, the MOC, and the filter (reported
as micrograms/actuation). FPF (Fine Particle Fraction)=[FPM/(sum of
sample content for throat assembly, cups 1-7, MOC, and the
filter)].times.100.
TABLE-US-00002 TABLE 2 NGI Particle Data for Albuterol sulfate
Total Ex-Valve Content FPM FPF mcg/actuation mcg/actuation % MDI
Test Point [SD] [SD] [SD] Example 1 Initial (Day 0) 189.1 [0.6]
109.4 [1.0] 65.6 [1.3] Example 1 5 weeks 175.9 [7.7] 98.1 [4.4]
63.8 [0.9] Example 2 5 weeks 175.8 [20] 100.9 [11.3] 64.4 [0.7]
TABLE-US-00003 TABLE 3 NGI Particle Data for Ipratropium Bromide
Total Ex-Valve Content FPM FPF mcg/actuation mcg/actuation % MDI
Test Point [SD] [SD] [SD] Example 1 Initial (Day 0) 31.4 [4.6] 15.4
[2.8] 56.0 [1.1] Example 1 5 weeks 29.2 [0.9] 13.9 [0.6] 53.8 [0.4]
Example 2 5 weeks 28.8 [3.6] 14.4 [1.8] 55.2 [0.4]
Example 3
[0168] Metered dose inhalers (MDIs) were prepared according to the
general procedure described in Example 1 using the formulation of
Table 4 with the exception that 50 microliter 3M Retention valves
with an EPDM elastomer seal (3M Corporation, Clitheroe, UK) and
actuators with a 0.5 mm orifice were used. The MDIs were stored in
an inverted orientation in a 4.degree. C./40.degree. C. cycling
chamber (cycling rate 6 hours) for a period of 9 weeks. MDIs were
tested for ex-actuator particle size distribution on the day
prepared (Day 0) and after 9 weeks of storage using the NGI study
procedure described above. In Table 5, the amount of albuterol
sulfate (micrograms/actuation) recovered from the valve stem,
actuator, and each stage of the NGI instrument (throat assembly,
cups 1-7, MOC, filter) is presented. In Table 6, the corresponding
particle size distribution data for ipratropium bromide is
presented.
TABLE-US-00004 TABLE 4 Suspension Formulation of Example 3
Formulation Ingredient Amount (in Percent by Weight) Albuterol
sulfate 0.173 Ipratropium Bromide Monohydrate 0.030 HFA-227
99.797
TABLE-US-00005 TABLE 5 NGI Test Results for Albuterol sulfate (MDI
of Example 3) Initial (Day 0) 9 weeks Test Component
(mcg/actuation) (mcg/actuation) Valve Stem 12.20 14.00 Actuator
13.60 14.50 Throat (USP Inlet) 28.30 28.30 Cup 1 0.42 0.63 Cup 2
1.29 1.51 Cup 3 5.22 5.50 Cup 4 23.10 21.30 Cup 5 21.40 18.80 Cup 6
4.06 3.42 Cup 7 1.01 1.17 MOC 0.74 0.63 Filter 2.18 3.14
TABLE-US-00006 TABLE 6 NGI Test Results for Ipratropium Bromide
(MDI of Example 3) Initial (Day 0) 9 weeks Test Component
(mcg/actuation) (mcg/actuation) Valve Stem 1.83 2.24 Actuator 2.74
2.77 Throat (USP Inlet) 5.92 6.65 Cup 1 0.14 0.17 Cup 2 0.61 0.68
Cup 3 1.70 1.72 Cup 4 3.71 3.39 Cup 5 1.94 1.79 Cup 6 0.30 0.30 Cup
7 0.09 0.13 MOC 0.08 0.09 Filter 0.09 0.15
Example 4
[0169] Metered dose inhalers (MDIs) were prepared according to the
general procedure described in Example 3 using the formulation of
Table 7. HFA-134a was used as the propellant in place of HFA-227.
The MDIs were stored in an inverted orientation in a 4.degree.
C./40.degree. C. cycling chamber (cycling rate 6 hours) for a
period of 6 weeks. MDIs were tested for particle size distribution
on the day prepared (Day 0) and after 6 weeks of storage using the
NGI study procedure described above. In Table 8, the amount of
albuterol sulfate (micrograms/actuation) recovered from the valve
stem, actuator, and each stage of the NGI instrument (throat
assembly, cups 1-7, MOC, filter) is presented. In Table 9, the
corresponding particle size distribution data for ipratropium
bromide is presented.
TABLE-US-00007 TABLE 7 Suspension Formulation of Example 4
Formulation Ingredient Amount (in Percent by Weight) Albuterol
sulfate 0.200 Ipratropium Bromide Monohydrate 0.035 HFA-134a
99.765
TABLE-US-00008 TABLE 8 NGI Test Results for Albuterol sulfate (MDI
of Example 4) Initial (Day 0) 6 weeks Test Component
(mcg/actuation) (mcg/actuation) Valve Stem 19.94 19.24 Actuator
17.01 15.87 Throat (USP Inlet) 33.19 28.09 Cup 1 0.47 0.57 Cup 2
0.79 0.81 Cup 3 3.67 3.60 Cup 4 21.75 20.03 Cup 5 22.98 21.84 Cup 6
4.81 4.79 Cup 7 1.25 1.41 MOC 0.94 0.93 Filter 2.25 3.62
TABLE-US-00009 TABLE 9 NGI Test Results for Ipratropium Bromide
(MDI of Example 4) Initial (Day 0) 6 weeks Test Component
(mcg/actuation) (mcg/actuation) Valve Stem 3.19 3.32 Actuator 3.42
3.06 Throat (USP Inlet) 7.90 6.58 Cup 1 0.10 0.13 Cup 2 0.25 0.24
Cup 3 1.20 1.14 Cup 4 4.32 4.00 Cup 5 2.87 2.70 Cup 6 0.51 0.53 Cup
7 0.17 0.22 MOC 0.16 0.19 Filter 0.22 0.27
Example 5
[0170] Metered dose inhalers (MDIs) were prepared according to the
general procedure described in Example 3 using the formulation of
Table 10. The bulk formulation for cold filling individual
canisters was prepared by combining albuterol sulfate and
ipratropium bromide monohydrate with a portion of the HFA-227
propellant (about half of the total propellant) in a vessel chilled
to less than -50.degree. C. The suspension was high shear mixed for
5-10 minutes using a Silverson mixer. The remaining propellant,
PVP-10 (polyvinylpyrrolidone, weight average molecular weight 10
kilodaltons), and ethanol were then added to the chilled vessel and
mixing was continued for an additional 10 minutes. The MDIs were
stored in an inverted orientation in a 4.degree. C./40.degree. C.
cycling chamber (cycling rate 6 hours) for a period of 6 weeks.
MDIs were tested for particle size distribution on the day prepared
(Day 0) and after 6 weeks of storage using the NGI study procedure
described above. In Table 11, the amount of albuterol sulfate
(micrograms/actuation) recovered from the valve stem, actuator, and
each stage of the NGI instrument (throat assembly, cups 1-7, MOC,
filter) is presented. In Table 12, the corresponding particle size
distribution data for ipratropium bromide is presented.
TABLE-US-00010 TABLE 10 Suspension Formulation of Example 5
Formulation Ingredient Amount (in Percent by Weight) Albuterol
sulfate 0.173 Ipratropium Bromide Monohydrate 0.030 PVP-10 0.010
Ethanol 1.000 HFA-227 98.787
TABLE-US-00011 TABLE 11 NGI Test Results for Albuterol sulfate (MDI
of Example 5) Initial (Day 0) 6 weeks Test Component
(mcg/actuation) (mcg/actuation) Valve Stem 13.41 14.26 Actuator
14.41 15.16 Throat (USP Inlet) 23.16 23.08 Cup 1 0.62 0.62 Cup 2
1.07 1.27 Cup 3 5.00 5.67 Cup 4 24.66 24.09 Cup 5 23.90 21.11 Cup 6
4.97 4.27 Cup 7 1.66 1.60 MOC 0.99 1.08 Filter 3.99 3.15
TABLE-US-00012 TABLE 12 NGI Test Results for Ipratropium Bromide
(MDI of Example 5) Initial (Day 0) 6 weeks Test Component
(mcg/actuation) (mcg/actuation) Valve Stem 2.37 2.46 Actuator 2.60
2.76 Throat (USP Inlet) 4.73 5.00 Cup 1 0.13 0.16 Cup 2 0.31 0.41
Cup 3 1.44 1.66 Cup 4 4.88 4.25 Cup 5 3.00 2.24 Cup 6 0.50 0.38 Cup
7 0.23 0.19 MOC 0.20 0.19 Filter 0.34 0.24
Example 6
[0171] Metered dose inhalers (MDIs) were prepared according to the
general procedure described in Example 5 using the formulation of
Table 13. The bulk formulation for cold filling individual
canisters was prepared by combining albuterol sulfate and
ipratropium bromide monohydrate with a portion of the HFA-227
propellant (about half of the total propellant) in a vessel chilled
to less than -50.degree. C. The suspension was high shear mixed for
5-10 minutes using a Silverson mixer (Silverson, East Longmeadow,
Mass.). The remaining propellant, Span-85 (sorbitan trioleate), and
ethanol were then added to the chilled vessel and mixing was
continued for an additional 10 minutes. The MDIs were stored in an
inverted orientation in a 4.degree. C./40.degree. C. cycling
chamber (cycling rate 6 hours) for a period of 6 weeks. MDIs were
tested for particle size distribution on the day prepared (Day 0)
and after 6 weeks of storage using the NGI study procedure
described above. In Table 14, the total Ex-valve content
(micrograms/actuation) and FPM (micrograms/actuation) are presented
for albuterol sulfate. In Table 15, the corresponding data for
ipratropium bromide is presented.
TABLE-US-00013 TABLE 13 Suspension Formulation of Example 6
Formulation Ingredient Amount (in Percent by Weight) Albuterol
sulfate 0.173 Ipratropium Bromide Monohydrate 0.030 Span-85 0.010
Ethanol 1.000 HFA-227 98.787
TABLE-US-00014 TABLE 14 NG1 Particle Data for Albuterol sulfate
Total Ex-Valve Content FPM MDI Test Point (mcg/actuation)
(mcg/actuation) Example 6 Initial (Day 0) 61.5 40.25 Example 6 6
weeks 54.31 37.31
TABLE-US-00015 TABLE 15 NG1 Particle Data for Ipratropium Bromide
Total Ex-Valve Content FPM MDI Test Point (mcg/actuation)
(mcg/actuation) Example 6 Initial (Day 0) 11.20 6.80 Example 6 6
weeks 9.70 6.06
Example 7
[0172] Metered dose inhalers (MDIs) were prepared using a 15 mL
deep drawn aluminum canister (internal surface coated with FEP), a
60 microliter 3M Retention valve with an EPDM elastomer seal, and a
0.4 mm orifice diameter actuator with a 0.8 mm jet length.
Albuterol sulfate and ipratropium bromide monohydrate were each
micronized to provide a mass median diameter (MMD) range of about
1-5 microns. The canisters were cold filled with a suspension
formulation composed of albuterol sulfate (0.312 weight percent),
ipratropium bromide monohydrate (0.052 weight percent), and HFA-227
(99.636 weight percent). MDIs were cold filled with the formulation
according to the filling procedure described in Example 1.
Example 8
[0173] Metered dose inhalers (MDIs) were prepared using a 15 mL
deep drawn aluminum canister (internal surface coated with FEP), a
60 microliter 3M Retention valve with an EPDM elastomer seal, and a
0.4 mm orifice diameter actuator with a 0.8 mm jet length.
Albuterol sulfate and ipratropium bromide monohydrate were each
micronized to provide a MMD range of about 1-5 microns. The
canisters were cold filled with a suspension formulation composed
of albuterol sulfate (0.314 weight percent), ipratropium bromide
monohydrate (0.052 weight percent), oleic acid (0.010 weight
percent), ethanol (1.000 weight percent) and HFA-227 (98.624 weight
percent). MDIs were cold filled with the formulation according to
the filling procedure described in Example 5 with oleic acid
replacing PVP-10 as the surfactant.
Example 9
[0174] Metered dose inhalers (MDIs) can be prepared using a 15 mL
deep drawn aluminum canister (internal surface coated with FEP), a
50 microliter 3M Retention valve with an EPDM elastomer seal, and a
0.4 mm orifice diameter actuator with a 0.8 mm jet length.
Albuterol sulfate and ipratropium bromide monohydrate can each be
micronized to provide a MMD range of about 1-5 microns. The
canisters can be cold filled with a suspension formulation composed
of albuterol sulfate (0.375 weight percent), ipratropium bromide
monohydrate (0.062 weight percent), and HFA-227 (99.563 weight
percent). MDIs can be cold filled with the formulation according to
the filling procedure described in Example 1.
Example 10
[0175] Metered dose inhalers (MDIs) can be prepared using a 15 mL
deep drawn aluminum canister (internal surface coated with FEP), a
50 microliter 3M Retention valve with an EPDM elastomer seal, and a
0.4 mm orifice diameter actuator with a 0.8 mm jet length.
Albuterol sulfate and ipratropium bromide monohydrate can each be
micronized to provide a MMD range of about 1-5 microns. The
canisters can be cold filled with a suspension formulation composed
of albuterol sulfate (0.377 weight percent), ipratropium bromide
monohydrate (0.063 weight percent), oleic acid (0.010 weight
percent), ethanol (1.000 weight percent) and HFA-227 (98.550 weight
percent). MDIs can be cold filled with the formulation according to
the general filling procedure described in Example 5 with oleic
acid replacing PVP-10 as the surfactant.
Example 11
[0176] Metered dose inhalers (MDIs) can be prepared using a 15 mL
deep drawn aluminum canister (internal surface coated with FEP), a
63 microliter 3M Retention valve with an EPDM elastomer seal, and a
0.4 mm orifice diameter actuator with a 0.8 mm jet length.
Albuterol sulfate and ipratropium bromide monohydrate can each be
micronized to provide a MMD range of about 1-5 microns. The
canisters can be cold filled with a suspension formulation composed
of albuterol sulfate (0.297 weight percent), ipratropium bromide
monohydrate (0.050 weight percent), and HFA-227 (99.653 weight
percent). MDIs can be cold filled with the formulation according to
the filling procedure described in Example 1.
Example 12
[0177] Metered dose inhalers (MDIs) can be prepared using a 15 mL
deep drawn aluminum canister (internal surface coated with FEP), a
63 microliter 3M Retention valve with an EPDM elastomer seal, and a
0.4 mm orifice diameter actuator with a 0.8 mm jet length.
Albuterol sulfate and ipratropium bromide monohydrate can each be
micronized to provide a MMD range of about 1-5 microns. The
canisters can be cold filled with a suspension formulation composed
of albuterol sulfate (0.299 weight percent), ipratropium bromide
monohydrate (0.050 weight percent), oleic acid (0.010 weight
percent), ethanol 1.000 weight percent) and HFA-227 (98.641 weight
percent). MDIs can be cold filled with the formulation according to
the filling procedure described in Example 5 with oleic acid
replacing PVP-10 as the surfactant.
Example 13
[0178] Suspension formulations A-M for use in metered dose inhalers
can be prepared with the compositions reported in Table 16. The
content of each component in a formulation is reported as the
weight percent. Albuterol sulfate and ipratropium bromide
monohydrate are each micronized to provide a MMD range of about 1-5
microns.
TABLE-US-00016 TABLE 16 Suspension Formulations Weight Percent of
the Formulation Component Albuterol Ipratropium Bromide Formulation
sulfate Monohydrate HFA-227 A 0.375 0.062 99.563 B 0.187 0.031
99.782 C 0.156 0.026 99.818 D 0.149 0.025 99.826 E 0.312 0.060
99.628 F 0.156 0.030 99.814 G 0.130 0.025 99.845 H 0.124 0.024
99.852 I 0.749 0.125 99.126 J 0.625 0.120 99.255 K 0.312 0.060
99.628 L 0.260 0.050 99.690 M 0.248 0.048 99.704
Example 14
[0179] Suspension formulations N-Z for use in metered dose inhalers
can be prepared with the compositions reported in Table 17. The
content of each component in a formulation is reported as the
weight percent. Albuterol sulfate and ipratropium bromide
monohydrate are each micronized to provide a MMD range of about 1-5
microns.
TABLE-US-00017 TABLE 17 Suspension Formulations Weight Percent of
the Formulation Component Albuterol Ipratropium sulfate Bromide
Formulation sulfate Monohydrate Oleic Acid Ethanol HFA-227 N 0.377
0.063 0.010 1.000 98.550 O 0.189 0.031 0.010 1.000 98.770 P 0.157
0.026 0.010 1.000 98.807 Q 0.150 0.025 0.010 1.000 98.815 R 0.314
0.060 0.010 1.000 98.616 S 0.157 0.030 0.010 1.000 98.803 T 0.131
0.025 0.010 1.000 98.834 U 0.125 0.024 0.010 1.000 98.841 V 0.755
0.126 0.010 1.000 98.109 W 0.629 0.121 0.010 1.000 98.240 X 0.314
0.060 0.010 1.000 98.616 Y 0.262 0.050 0.010 1.000 98.678 Z 0.250
0.048 0.010 1.000 98.692
* * * * *